Project Summary Obstructive sleep apnea (OSA) is a major source of cardiovascular morbidity and mortality for which conventional treatment is poorly tolerated and effective pharmacotherapy is lacking. Efforts to develop pharmacotherapy have been hindered by a lack of fundamental insight into neuromuscular mechanisms causing upper airway obstruction during sleep. Our proposal will address this gap by elucidating distinct effects of lingual muscles on upper airway patency in OSA patients. Our central hypothesis is that synergistic effects of lingual muscles are required to overcome specific defects in upper airway structural and neuromotor control and restore pharyngeal patency. This hypothesis challenges the long-held concept that the genioglossus is a major pharyngeal dilator muscle responsible for the maintenance of pharyngeal patency during sleep. It rests instead on strong evidence that several lingual and pharyngeal muscles control distinct mechanical determinants of pharyngeal patency during sleep. In SA1, we will elucidate specific mechanisms for synergistic control of pharyngeal patency by stimulating lingual protrudor and retractor muscles, and will elucidate distinct physiologic mechanisms for synergy between these muscle groups during drug-induced sleep endoscopy (DISE, SA1). In SA2, we will determine the impact of lingual muscle synergy on the maintenance of airway patency in NREM and REM sleep. In both SAs, we will test the impact of anatomic constraints on stimulation responses. We hypothesize that protrudors are required to decompress peri-pharyngeal tissues and dilate the pharynx, whereas co-activation with retractors further decrease pharyngeal collapsibility by stiffening the tongue and fixing its position. Our aims challenge the primacy of the genioglossus in the maintenance of airway patency during sleep. The project seeks to develop novel strategies for targeting specific defects in the control of pharyngeal patency by activating specific lingual muscles that relieve pharyngeal obstruction during sleep. This project outlines rigorous approaches for establishing synergistic mechanisms between lingual protrudors and retractors, based on our proven ability to activate these muscles independently. State of the art physiologic and imaging methods will be deployed to probe effects of muscle stimulation, sleep state, and anatomy on the control of pharyngeal patency. Our findings will (1) transform our understanding of upper airway neuromuscular control during sleep, (2) establish relevant neuromotor targets for electro-stimulation and pharmacotherapy, and will (3) identify potential physiologic and anatomic predictors of therapeutic success when these strategies are deployed. In leveraging a unique combination of translational approaches, we will demonstrate specific strategies for activating lingual muscles and stabilizing airway patency during sleep in apneic patients.